Lisa G. Winston, MD         

University of California, San Francisco/ Zuckerberg San Francisco General

Disclosures I have nothing to disclose

Community‐Acquired Pneumonia (CAP) ‐ Outline

Epidemiology

Diagnosis

Microbiology

Risk stratification

Treatment

Prevention

Community‐Acquired Pneumonia Guidelines

Diagnosis and treatment of adults with community‐acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America

Update of 2007 guidelines

Different format and approach but few changes in management

Am J Respir Crit Care Med 2019 Oct 1;200:e45

Epidemiology: Acute Lower Respiratory Tract Infections

In U.S., influenza and pneumonia 8th most common cause of death per the Centers for Disease Control and Prevention (moved up from 9th in 2010)

55,672 deaths in 2017

Most common cause of death from infectious disease

Among those 85 and older, at least 1 in 20 hospitalized each year

Epidemiology: Acute Lower Respiratory Tract Infections

Inpatient mortality rate: may be influenced by coding

From 2003 – 2009, mortality rate for principal diagnosis pneumonia decreased from 5.8% to 4.2%

More patients coded with principal diagnosis sepsis or respiratory failure and secondary diagnosis pneumonia

Using all codes, little change in mortality rate

Lindenauer et al, JAMA 2012;307:1405‐13

Outpatient mortality < 1%; about 80% of CAP treated in outpatient setting

Diagnosis Chest radiograph – needed in all cases?

Avoid over‐treatment with antibiotics 

Differentiate from other conditions

Specific etiology, e.g. tuberculosis

Co‐existing conditions, such as lung mass or pleural effusion

Evaluate severity, e.g. multilobar 

Unfortunately, chest physical exam not sensitive or specific and significant variation between observers 

Arch Intern Med 1999;159:1082-7

Microbiological Investigation

Sputum Gram stain and culture 30‐40% patients cannot produce adequate sample 

Most helpful if single organism in large numbers

Culture (if adequate specimen): antibiotic sensitivities

Limited utility after antibiotics for most common organisms

Usually unnecessary in outpatients – 2019 guideline recommends against

May be most helpful in severe CAP and/or when treatment for MRSA or P. aeruginosa is considered

Severe Pneumonia

Am J Respir Crit Care Med 2019 Oct 1;200:e45

Obtain blood cultures?

Not recommended in outpatients

Obtain prior to antibiotics

Positive in 5 – 14% of hospitalized patients

Obtain with severe disease ‐most important predictor

2019 guidelines also recommend when empirically treating for MRSA or P. aeruginosa

Legionella and Pneumococcal Urinary Antigen Testing? 

Evaluation for Legionella Urinary antigen test for L. pneumophila serogroup 1 (70‐90%)

Can also culture with selective media

Probably most helpful in severe disease or with epidemiologic risk (e.g., recent travel, suspected outbreak)

Pneumococcal urinary antigen test Simple, takes about 15 minutes

In adults, sensitivity 50‐80%, specificity ~90%

Consider in severe CAP

Other Microbiological Investigation?

Influenza testing

Treatment likely provides benefit for many

Test when influenza is circulating in the community

Multiplex PCR systems for respiratory pathogens

Benefit uncertain

Procalcitonin?

Procalcitonin is produced in response to endotoxin and endogenous mediators released in the setting of bacterial infections

Rises in bacterial infections much more than, e.g., viral infections or inflammatory states

Rises and falls quickly

Procalcitonin‐guided treatment in acute respiratory infections may decrease antibiotic exposure and might improve outcomes, particularly in the ICU

Decreased antibiotic exposure was not seen in large ED RCT

Not recommended to guide decision to start antibiotics

New Engl J Med 2018;379:236-249Lancet Infect Dis 2018;18:95-107

Etiology – historical data Clinical syndrome and CXR not reliably predictive

Streptococcus pneumoniae 20‐60%

Haemophilus influenzae 3‐10%

Mycoplasma pneumoniae up to 10%

Chlamydophila pneumoniae up to 10%

Legionella up to 10%

Enteric Gram negative rods up to 10%

Staphylococcus aureus up to 10%

Viruses up to 10%

No etiologic agent 20‐70%

CAP Surveillance Study Adults hospitalized with CAP at 5 hospitals in Chicago and Nashville

Extensive diagnostic testing done via culture, serology, antigen testing, and molecular diagnostics

A pathogen was detected in only 38% of patients with specimens available Viruses 62%

Bacteria 29%

Bacteria and virus 7%

Fungus or mycobacteria 2%

NEJM 2015;373:415-27

Typical vs. AtypicalTypical 

Visible on Gram stain, grows in routine culture

Susceptible to beta lactams 

S. pneumoniae, H. influenzae

Atypical Not visible on Gram stain, special culture techniques

Not treated with beta lactams

M. pneumoniae, C. pneumoniae, Legionella

X X

S. pneumoniaeRisk factors

Extremes of ageAlcoholismCOPD and/or smokingNursing home residence

InfluenzaInjection drug useAirway obstructionHIV infection

Legionella Think about with severe disease, high fever, hyponatremia, markedly elevated LDH, CNS abnormalities

Fluoroquinolone or azithromycin drug of choice; usual rx 14‐21 days

Risk factors:

Older ageSmokingImmune compromise,

cell mediatedTravel

Renal diseaseLiver diseaseDiabetesMalignancy

Mycoplasma pnuemoniae Common cause respiratory infections in children/young adults

Pneumonia relatively uncommon

Epidemics in close quarters

May have sore throat, nausea, vomiting, hemolytic anemia, rash

Treatment with doxycycline, macrolide, or fluoroquinolone

Rising rate of macrolide resistance – U.S. 8.2%; China 90%

Pediatr Infect Dis J 2012;31:409-11

• Outpatient vs. inpatient?• Cost• Patient satisfaction• Safety

Risk Stratification

Risk Stratification – Pneumonia Severity Index

Outpatient vs. inpatient? Pneumonia Patient Outcomes Research Team (PORT) study (Fine et al, NEJM 1997;336:243‐250) Prediction rule to identify low risk patients with CAP

Stratify into one of 5 classes Class I: age < 50, none of 5 co‐morbid conditions, apx. normal VS, normal mental status

Class II‐V: assigned via a point system

Risk Stratification – Pneumonia Severity Index

Mortality < 1% for classes I, II

Low risk patients hospitalized more than necessary

Caveats:

Does not take into account social factors

Pneumonia Severity Index Calculator

https://www.mdcalc.com/psi-port-score-pneumonia-severity-index-cap

Age and sex; resident of nursing home {yes/no}

Comorbid diseases {yes/no}: renal disease, liver disease,CHF, cerebrovascular disease, neoplasia

Physical exam {yes/no}: altered mental status, SBP < 90,temp < 35 or >=40, RR>=30, HR>=125

Labs/studies {yes/no}: pH<7.35, PO2<60 or Sat<90, Na<130, HCT<30, gluc>250, BUN>30, pleural eff

Patient #1

60 year‐old man with diabetes presents with fever and dyspnea.  Positive PORT items include HR=130, Na=129, glucose=300.

Should this patient be hospitalized?

Please vote:   1. Yes

2. No

Pneumonia Severity Index Results

Risk Class Score MortalityLow I < 51 0.1%Low II 51 - 70 0.6%Low III 71 - 90 0.9%Medium IV 90 - 130 9.5%High V > 130 26.7%

Hospitalization is recommended for class IV and V. Class III should be based on clinical judgment.

Class: IVScore: 100

Patient #2

55 year-old woman with no other risk factors?Hospitalization? Please vote:

1. Yes2. No

Class : IIScore : 45Mortality : 0.1%

Patient #392 year-old man with no other risk factors?Hospitalization? Please vote:

1. Yes2. No

Class : IVScore : 92Mortality : 9.5%

Patient #4

20 year-old woman with SBP < 90 and a pleural effusion?

Hospitalization? Please vote:1. Yes2. No

Class : IIScore : 40Mortality : 0.6%

Other Scoring Systems

CURB‐65 (British Thoracic Society)

Has only 5 variables, compared with 20 for Pneumonia Severity Index

Is coverage of “atypical” organisms important?

In Europe, amoxicillin commonly used as a single drug with data supporting a short course (3 days in responding patients)

Some studies show no benefit of empirical atypical coverage on survival or clinical efficacy in hospitalized patients

el Moussaoui et al, BMJ 2006;332:1355 - 62

Shefet et al, Arch Intern Med 2005;165:1992-2000

JAMA 2014;311(21):2199-2208

• V.A. retrospective, cohort study of patients 65 and older hospitalized with pneumonia 2002-2012

• 31,863 patients treated with azithromycin compared with 31,863 propensity matched patients with no exposure

• 90 day mortality significantly lower 17.4% vs. 22.3%, O.R. 0.73 • Myocardial infarct significantly higher 5.1% vs. 4.4%, O.R. 1.17

NEJM 2015;372:1312-23

• Cluster-randomized trial in 7 hospitals in the Netherlands with rotating strategies• Adults with CAP not requiring ICU• Beta-lactam alone (656 patients) vs. beta-lactam plus macrolide (739 patients)

vs. fluoroquinolone alone (888 patients)• Primary outcome 90-day mortality: beta-lactam monotherapy non-inferior to

other strategies• No difference in length of stay or complications

JAMA 2016;315:593-602

• Two RCTs evaluated beta-lactam + macrolide combination therapy vs. beta-lactam monotherapy – includes study prior slide• One failed to demonstrate non-inferiority of monotherapy

• 6 of 8 observational studies favored beta-lactam + macrolidecombination therapy vs. beta-lactam monotherapy

• 3 of 3 observational studies favored fluoroquinolone monotherapyover beta-lactam monotherapy

*Based on these data, 2019 guidelines do not recommend beta-lactammonotherapy for inpatients

Antibiotic Treatment: Outpatient

Without co‐morbidities or risk factors for resistant organisms

Amoxicillin 1 g three times daily

Doxycycline 100 mg twice daily

Azithromycin or clarithromycin, if pneumococcal resistance < 25%

With co‐morbidities or risk factors for resistant organisms Amoxicillin/clavulanate or cephalosporin (cefuroxime or cefpodoxime) plus a macrolide or doxycycline

Respiratory fluoroquinolone: moxifloxacin, gemifloxacin, or levofloxacin (750 mg daily)

Antibiotic Treatment: Outpatient

Data to guide antibiotic selection are limited

Available studies suggest good outcomes with few differences 

Co‐morbidities include heart, lung, liver, renal disease; diabetes, alcohol use disorder, malignancy, asplenia

Risk factors for resistance include previous MRSA or P. aeruginosa from respiratory culture or recent hospitalization with parenteral antibiotics (in last 90 days) 

Lefamulin and omadacycline not added due to cost, tolerability, and less experience

Editorial comment: Not clear why combination therapy does not include amoxicillin as a beta‐lactam option

Antibiotic Treatment: Inpatient, Nonsevere

Standard • Beta-lactam (ampicillin/sulbactam, cefotaxime, ceftriaxone, or ceftaroline) + macrolide OR

• Respiratory fluoroquinolone

Prior respiratory isolation MRSA

Add MRSA coverage and obtain respiratory cultures and/or nasal PCR to allow for de-escalation or continuation

Prior respiratory isolation P. aeruginosa

Add P. aeruginosa coverage and obtain respiratory cultures to allow for de-escalation or continuation

Recent hosp with IV abx and local risk factors MRSA

Obtain respiratory cultures and/or nasal PCR; add coverage if positive

Recent hosp withIV abx and local risk factors P. aeruginosa

Obtain respiratory cultures; add coverage if positive

Antibiotic Treatment: Inpatient, Nonsevere

Guidance beyond standard regimen intended to help with circumstances previously covered by healthcare‐associated pneumonia (HCAP) guidelines

More circumspect / influenced by antimicrobial stewardship

Doxycycline, instead of a macrolide, included as a conditional recommendation in combination with a beta‐lactam

Limited data

No need for specific anaerobic coverage with suspected aspiration pneumonia

Outside the ICU…we love doxycycline Adult inpatients June 2005 – December 2010

Compared those who received ceftriaxone + doxycycline to those who received ceftriaxone alone

2734 hospitalizations: 1668 no doxy, 1066 with doxy

Outcome: CDI within 30 days of doxycycline receipt

CDI incidence 8.11 / 10,000 patient days in those receiving ceftriaxone alone; 1.67 / 10,000 patient days in those who received ceftriaxone and doxycycline 

Doernberg et al, Clin Infect Dis 2012;55:615-20

Antibiotic Treatment Inpatient, SevereStandard • Beta-lactam (ampicillin/sulbactam, cefotaxime, ceftriaxone, or

ceftaroline) + macrolide OR• Beta-lactam + respiratory fluoroquinolone

Prior respiratory isolation MRSA

Add MRSA coverage and obtain respiratory cultures and/or nasal PCR to allow for de-escalation or continuation

Prior respiratory isolation P. aeruginosa

Add P. aeruginosa coverage and obtain respiratory cultures to allow for de-escalation or continuation

Recent hosp with IV abx and local risk factors MRSA

Add MRSA coverage and obtain respiratory cultures and/or nasal PCR to allow for de-escalation or continuation

Recent hosp withIV abx and local risk factors P. aeruginosa

Add P. aeruginosa coverage and obtain respiratory cultures to allow for de-escalation or continuation

What about steroids?

Lancet 2015: http://dx.doi.org/10.1016/S0140-6736(14)62447-8

• Randomized, double blind trial in Switzerland• 785 adult inpatients received 50 mg prednisone daily x 7 days or placebo• Primary outcome clinical stability: 3.0 days prednisone vs. 4.4 days placebo,

p<.0001• Time to hospital discharge 6 days prednisone vs. 7 days placebo, p=.01• No difference complications except slightly higher in-hospital hyperglycemia

with prednisone

Questions re study 2911 patients assessed to randomize 802

Why was length of stay so long?

4% prednisone and 6% placebo admitted to ICU

Death from any cause 4% prednisone and 3% placebo

What about steroids?

Multicenter, double‐blind, RCT at 3 hospitals in Spain

Adults with severe CAP (75% in ICU) 

Methylprednisolone 0.5 mg/kg q 12h x 5 days (n=61) vs. placebo (n=59)

Recruited 2004 – 2012

Primary outcome: treatment failure (composite) 13% vs. 31%, P=.02

Mortality 10% vs. 15%, P=.37

JAMA 2015;313(7):677-86

What about steroids?

Systematic review and meta‐analysis of steroids for patients hospitalized with CAP

Included 13 RCTs with 2005 patients total

Both studies on previous slides included

Outcomes: 

Possible 2.8% reduction in mortality

5% reduction mechanical ventilation 

1 day decrease hospital stay 

3.5% increase in hyperglycemia requiring treatment

Ann Intern Med 2015;163(7):519-28

What about steroids? At least 2 multicenter trials with data anticipated

ESCAPe:  patients with severe CAP, VA hospitals, methylprednisolone

Study completed; results not yet reported

CAPE_COD:  patients with severe CAP, French hospitals, hydrocortisone

Recruitment in progress

Guidelines do not recommend steroids

Can be considered with refractory septic shock

https://clinicaltrials.gov/

Length of Therapy

7 – 10 days had been standard but probably not necessary

Convincing data for 5‐day course with azithromycin or high dose levofloxacin

Meta‐analysis: patients with mild to moderate disease can be treated with 7 days or less

Guidelines suggest 5 days appropriate for most patients

Am J Med. 2007;120(9):783-90

Switch to Oral Therapy Reduces costs, shortens length of stay, may reduce complications

As soon as improving clinically, able to take POs, GI tract functioning Usually within 3 days; no need to observe in hospital

Empirical therapy:  macrolide, doxycycline, respiratory fluoroquinolone, or combination therapy 

Amoxicillin if susceptible organism, usually S. pneumoniae, identified

Prevention

There are stepspatients and providerscan take….

Prevention

Vaccination Influenza vaccine

Pneumococcal vaccines

Smoking cessation Smoking, with or without COPD, is a significant risk factor

But, what happened to healthcare‐associated pneumonia (HCAP)?

Am J Respir Crit Care Med 2005;171:388-416

The concept of HCAP has been removed – why?• Increasing evidence that most patients with HCAP are not at

high risk for resistant pathogens• Other features besides exposure to the healthcare system

may be important• May be covered by new CAP guidelines However, concept of HCAP as an entity not maintained

Practical tips for HCAP

Most patients with “HCAP” can be treated like CAP

Consider expanded initial therapy if

Severely ill

History of resistant organism or other risk factors such as extensive antibiotic exposure

Knowledge of local flora/resistance patterns is helpful

If using expanded therapy, prioritize microbiologic diagnosis

De‐escalate based on results 

2016 guidelines: take home points for both HAP and VAP

Perform microbiologic testing – preferred over empirical therapy

Obtain non‐invasively – expectorated, induced sputum, endotracheal aspirate

BAL, mini‐BAL, protected‐brush specimens not recommended

Not recommended for decision to initiate therapy

Procalcitonin

C‐reactive protein

Clinical Pulmonary Infection Score (CPIS)

Most patients should be treated for 7 days

2016 guidelines: initial treatment of HAP (based on very low quality evidence) Use local pathogen and antibiotic resistance data

Cover MRSA in selected patient

Prior IV antibiotics within 90 days

> 20 of S. aureus isolates on unit are MRSA

High risk of mortality

Cover Pseudomonas aeruginosa

Double coverage of P. aeruginosa with risk factors

Prior IV antibiotics within 90 days

High risk for mortality

2016 guidelines: initial treatment of HAP (based on very low quality evidence)

Not at high risk of mortality and no risk factors increasing likelihood of MRSA (cover MSSA and P. aeruginosa)

One of the following:

Piperacillin‐tazobactam 4.5 g IV q 6h

Cefepime 2 g IV q 8h

Levofloxacin 750 mg IV daily

Imipenem 500 mg IV q 6h

Meropenem 1 g IV q 8h

2016 guidelines: initial treatment of HAP (based on very low quality evidence) Not at high risk of mortality but increased risk of MRSA:

Piperacillin‐tazobactam 4.5 g IV q 6h

Cefepime 2 g IV q 8h

Levofloxacin 750 mg IV daily

Imipenem 500 mg IV q 6h

Meropenem 1 g IV q 8h

Aztreonam 2 g IV q 8h

PLUS

Vancomycin 15 mg/kg IV q 8h‐12h (goal trough 15 – 20) OR

Linezolid 600 mg IV q 12h

2016 guidelines: initial treatment of HAP (based on very low quality evidence)

High risk of mortality or IV antibiotics with 90 days:

Antipsuedomonal beta lactam: piperacillin‐tazobactam, cefepime, ceftazidime, aztreonam, imipenem, meropenem

PLUS

A second antipseudomonal antibiotic: levofloxacin, ciprofloxacin, amikacin, gentamicin, tobramycin 

PLUS

Vancomycin or linezolid

2016 guidelines: initial treatment of VAP 

Use local pathogen and antibiotic resistance data

Do not treat ventilator‐associated tracheobronchitis with antibiotics

2016 guidelines: initial treatment of VAP (based on very low quality evidence) Cover S. aureus, P. aeruginosa, and other Gram‐negative bacilli in all empirical regimens

Cover MRSA with vancomycin or linezolid when > 10 – 20% of S. aureus isolates in unit are MRSA

Use two antipseudomonal antibiotics if

• Prior IV antibiotic use within 90 days• Septic shock• ARDS preceding VAP• 5 or more days of hospitalization preceding VAP

• > 10% of Gram negative isolates resistant to planned monotherapy

• Susceptibility rates unknown

ZSFG / SF VAMC HAP and VAP antibiotic guideline: initial therapy

Mild HAP: ceftriaxone or ertapenem or levofloxacin

Severe HAP (e.g. high O2 requirement, cavitary disease): vancomycin plus cefepime or piperacillin/tazobactam

VAP, intubated < 5 days without complications (e.g. multifocal or cavitary disease): ceftriaxone or ertapenem or levofloxacin

VAP, intubated > 5 days or complicated: vancomycin plus cefepime or piperacillin/tazobactam